1. Field of Invention.
This invention relates to a novel process for the preparation of azetidine and 2 or 3-methyl and ethyl azetidine free bases starting with an .alpha.-substituted arylmethyl amines and an appropriate propane derivative having leaving groups in the 1 and 3 positions. The invention encompasses novel intermediates, use thereof, and methods of preparation and a novel method of obtaining the azetidines in free base form from their mineral acid salts.
2. Information Disclosure Statement.
Azetidine is available commercially only in small quantities. Szmuszkovicz, J., et al. in J. ORG. CHEM. (1981) 46, 3562-3564 prepared azetidine by heating tri-n-butylphosphoranilidine-1-propanol. They also discussed the work of others wherein azetidine has been prepared by reacting toluenesulfonamide and 1-bromo-3-chloropropane to obtain 1-tosylazetidine followed by reaction with lithium and wherein azetidine and 2 or 3-methyl or ethyl azetidines have been prepared by heating the appropriate 1-(2-carbethoxyethyl)azetidine together with potassium hydroxide.
More recently, but subsequent to the present invention, Nitta, Y. and Kanamori, Y., in HETEROCYCLES, Vol. 24, No. 9 (1986) pp 2467-2470 disclosed our novel 1-(diphenylmethyl)azetidine chemical intermediates and the preparation of the hydrochloride salt of azetidine therefrom. The 1-benzhydrylazetidine was prepared from tosylated-1-(benzhydryl)-3-azetidinol and sodium borohydride. That process employs entirely different starting materials and route from that of the present invention. The Nitta and Kanamori method employs leaving groups on the 2 or 3 position of the azetidine ring, which the present process does not. In addition, the process of the present invention provides a method of obtaining azetidine free base in vapor or liquid forms, which the disclosure of Nitta and Kanamori does not.
The present invention stems in part from our discovery that water in, or added to, a heated reaction mixture comprised of an .alpha.-substituted-arylmethylamine, a 1,3-dihalopropane, a non-nucleophilic base and an organic solvent induces progressive cyclization of linear intermediates as they are formed, in the same reaction mixture, to give the 1-(.alpha.-substituted-arylmethyl)azetidine which is the required precursor to the azetidine free base product of our overall process. In the absence of water, cyclization does not occur and uncyclized 3-(.alpha.-substituted-arylmethylamino)propyl halide and/or various dimers may result, for example, 1,3-bis-benzhydrylaminopropane. While the starting primary and intermediate secondary amines and the 1-(.alpha.-substituted-arylmethyl)azetidine are basic in nature, they are not capable of inducing the required cyclization to azetidine and addition of non-nucleophilic base is a requirement in the present process.
As is well known in the art, azetidine free base has great affinity for its solvents and tends to codistill with the solvent. It is also well known that azetidine free base tends to polymerize if left in contact with neutralizing agents. The present method of converting a mineral acid salt to azetidine free base overcomes these difficulties by providing a novel flash evaporating technique for an azetidine from an agitated mobile concentrated basic medium in which the azetidine salt in aqueous solution is quickly neutralized and is flash distilled out before the azetidine free base polymerizes. The solvent is undistilled for the most part due to its affinity for the remaining basic residue.
Azetidine and 2 and 3-methyl and ethyl azetidine free bases (Formula I below) have utility in the preparation of pharmaceutical agents; for example, in direct azetidination of a cycloalkanone as described in U.S. Pat. No. 4,540,690.
Prior to the present invention, no practical method suitable to scaled-up production of liquid azetidine free base, relatively free of solvent, was available.